This invention relates to long-acting antiparasitic formulations containing doramectin, suitable for parenteral administration, e.g. by subcutaneous or intramuscular injection to animals such as cattle, sheep, swine, etc., and which are useful in the treatment of conditions caused by endo- and/or ectoparasites.
Doramectin (the active ingredient in Dectomax(trademark)) is a potent parasiticide sparingly soluble in water, described by AC Goudie et al, in Vet. Parasitol. 49(1) (July 1993). Injectable formulations of doramectin in sesame oil/ethyl oleate were disclosed in EP 0 393 890, and discussed by S R Wicks et al, in Vet. Parasitol. 49(1) (July 1993). Doramectin is effective in the treatment of parasites such as those mentioned in the above publications, herein incorporated by reference in their entirety. Such parasites can harm livestock animals and can cause severe economic losses.
Long acting injectable formulations of avermectins in hydrophobic carriers and small amounts of hydrogenated castor oil were disclosed in EP 0 535 734, and in triacetin in EP 0 413 538.
We have now discovered formulations of doramectin which have long duration of action in vivo, and which have beneficial properties e.g. injection site tolerability, stability on storage, acceptable viscosity, syringeability across a wide temperature range, and good bioavailability. The relatively high levels of doramectin possible in these formulations enables administration of low volumes of formulation, without loss of the beneficial properties mentioned above.
According to the invention there are provided formulations comprising doramectin at about 1-11% w/v, in a solvent comprising castor oil at about 25-80% v/v and either
(i) ethyl oleate at about 20-75% v/v, or
(ii) fractionated coconut oil at about 20-75% v/v, and
(iii) optional further auxiliaries.
Castor oil is the fixed oil obtained from the seed of Ricinus communes L. (fam. Euphorbiaceae). It is a clear, almost colourless or slightly yellow, viscid liquid. See e.g. USP 23 and Ph.Eur.xe2x80x94Official Monographs. There are various commercial sources of this material. It has long been known as an ingredient in parenteral, i.e. injection formulations (e.g. see Martindalexe2x80x94the Extra Pharmacopoeia, The Royal Pharmaceutical Society, 30th edition; Encycopaedia of Pharmaceutical technology, vol 8, ed. J Swarbrick and J C Boylan, 1993, Marcel Dekker; Handbook of Pharmaceutical Additives, p.395, M. Ash et al, Gower Publishing Ltd. 1995; A J Spiegel and M M Noseworthy, J. Pharm. Sci, October 1963, vol.52, no.10, 917; European Patent Application publication no. 0 140 255 A2 (Sumitomo); R Deansly et al, J. Physiol., 78, 155, 1933; G J Brewer et al, Pharmacology (1981) 23:254; M-A Mackey et al, Human Reproduction, vol. 10, no.4, 862 (1995); British Patent 1,126,892 (Schering); European Patent Application publication no.0 211 691 A2 (Eli Lilly and Co.); Canadian Patent 1 237 672 (Bayer Aktiengesellschaft); International Patent Application publication number WO 95/26291 (Boehringer Ingelheim); etc.). Injection formulations based on castor oil have been commercialised for a number of drug substances, for example the immunosuppressant macrolide tacrolimus (Prograf/Fujiswawa, FK-506).
Ethyl oleate [CAS no.: 111-62-6] is available commercially, for example from Croda Oleochemicals. The commercial product is a pale yellow oil with a maximum acid value of 0.5 mgKOH/g, an ester value of 100-105%, an iodine value of 75-85 g/100 g, specific gravity of 0.866-0.874 kg/l at 25 degrees centigrade, and may sometimes contain an antioxidant such as butylhydroxyanisole (BHA) at approximately 0.01%.
By xe2x80x9cfractionated coconut oilxe2x80x9d is meant the fraction of coconut oil containing propylene glycol octanoic/decanoic diester, with typical C6 fatty acid content of at most ca. 3%, C8 approximately 65-80%, C10 approximately 10-30% and C12 at most 3%, an acid number of at most 0.1, saponification number of approx. 320 to 340 and an iodine number of at most 1, or a reconstituted mixture having substantially the same composition as said fraction. An example of the fractionated coconut oil which can be used in the formulations according to the invention is sold under the name Miglyol(trademark) 840 (Huls).
The formulations of the invention are useful in the treatment of economically important parasite infections, including endo-parasites such as gastrointestinal roundworms, i.e. nematodes (e.g. Cooperia sp.), lungworms (Dictyocaulus viviparus), and other endo-parasites mentioned in EP 0 393 890. The formulations are also useful in the treatment of ecto-parasites such as arthropods such as ticks, mites, lice, fleas, blowfly, biting insects, migrating dipterous larvae, etc.
Formulations within the scope of the invention have been shown to provide efficacy against economically important endo-parasites at up to 4 months, and ecto-parasites at up to 3 months, following a single injection. This represents a significant advantage for those working in the field of livestock animals as it offers effective treatment with one application per season.
One preferred group of formulations is where the castor oil is present in the solvent at about 55-75% v/v.
Preferably the amount of doramectin is 3-9% w/v, more preferably about 5-9% w/v, and most preferably about 6% w/v of the total formulation.
Preferably the solvent is selected from castor oil/ethyl oleate (from 2:3 v/v to 2:1 v/v, especially 2:3 v/v to 3:2 v/v) and castor oil/fractionated coconut oil (from 2:7 v/v to 4:7 v/v).
Optionally the formulations may contain further auxiliaries generally used in pharmaceutical or veterinary injectable formulations in small amounts, such as a free radical scavenger antioxidant e.g. BHA, a preservative such as phenol, m-cresol, etc.
Preferred specific formulations are those mentioned in the Examples below, especially those of Examples 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, 1C, 2C and 3C.
Another aspect of the invention is a method of treatment of a condition caused by an endo- or ectoparasite by administration of an effective amount of a formulation according to the invention.
Another aspect of the invention is a formulation according to the invention for use in medicine.
Another aspect of the invention is the use of a formulation according to the invention in the manufacture of a medicament for the treatment of conditions caused by endo- or ecto-parasites.
Formulations according to the invention can be made by standard methods, in accordance with standard pharmaceutical or veterinary practice. For example the doramectin (and optional other constituents) can be dissolved in the solvent mixture, sterilised and packed in a manner well-known in the art.
The invention is illustrated by the following examples, wherein xe2x80x9cFCOxe2x80x9d is fractionated coconut oil [Miglyol(trademark) 840 (Huls)], and xe2x80x9cEOxe2x80x9d is ethyl oleate.